Methods and compositions for treating or preventing sleep disturbances and associated illnesses using very low doses of cyclobenzaprine

ABSTRACT

The present invention relates to methods and compositions comprising a very low dose of cyclobenzaprine or metabolite thereof for preventing and treating sleep disturbances and illnesses manifested with sleep dysfunction including fibromyalgia syndrome, chronic fatigue syndrome, sleep disorders, psychogenic pain disorders or chronic pain syndromes or symptoms thereof. The present invention further relates to methods and compositions for treating sleep disturbances, chronic pain or fatigue in humans suffering from fibromyalgia syndrome, chronic fatigue syndrome, sleep disorders, psychogenic pain disorders, chronic pain syndromes using a very low dose of cyclobenzaprine.

TECHNICAL FIELD OF THE INVENTION

[0001] The invention relates to methods and compositions comprising verylow doses of cyclobenzaprine. The methods and compositions are usefulfor treating or preventing sleep disturbances. Particularly, the methodsand compositions of this invention are useful for treating patientssuffering from fibromyalgia syndrome, prolonged fatigue, chronicfatigue, chronic fatigue syndrome, sleep disorders, psychogenic paindisorders, chronic pain syndromes, autoimmune diseases and symptomsthereof.

BACKGROUND OF THE INVENTION

[0002] 1.1 Cyclobenzaprine

[0003] Cyclobenzaprine or3-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine, isrepresented by the chemical formula:

[0004] Cyclobenzaprine was first synthesized in 1961. [Villani, F. J.,et al., “Dialkylaminoalkyl derivatives of 10,11-dihydro-511-dibenzo a,dcycloheptene and related compounds,” J. Med. Pharm. Chem. 5:373-383(1962)]. Cyclobenzaprine was approved by the U.S. Food and DrugAdministration in 1977 for the treatment of acute muscle spasms of localorigin. [Katz, W., et al., “Cyclobenzaprine in the Treatment of AcuteMuscle Spasm: Review of a Decade of Clinical Experience,” ClinicalTherapeutics 10:216-228 (1988)]. Cyclobenzaprine is sold as ahydrochloride salt in a 10 mg non-scored tablet under the tradenameFlexeril® (Merck and Co.) or as a generic (Genera, Warner-Chilcott,Duramed, Mylan, Endogenerics, and Watson) for use as a skeletal musclerelaxant. The pharmacokinetics of cyclobenzaprine metabolism have beenwell studied (e.g., Katz, et al., page 219, supra).

[0005] No indications of organ toxicity were found incyclobenzaprine-treated patients at recommended doses. Toxic effectswere reported, however, for three individuals who ingested between 260to 900 mg of cyclobenzaprine. [Katz, et al., “Cyclobenzaprine in theTreatment of Acute Muscle Spasm: Review of a Decade of ClinicalExperience,” Clinical Therapeutics 10:216-228 (1988)].

[0006] The principal side effects of cyclobenzaprine treatment aredrowsiness, dry mouth or tongue, dizziness and bad taste. [Katz, W. A.,et al., supra.] Other less common side effects include nausea,tiredness, constipation, blurred vision, nervousness, confusion,abdominal pain and discomfort. Although cyclobenzaprine use has beenreported to be associated with the side effects of drowsiness ortiredness, the utility of cyclobenzaprine as an agent for improving thequality of sleep, being a sleep deepener, or treating sleep disturbanceswhen administered using a very low dosage regimen has not beenrecognized.

[0007] 1.2 Sleep and Sleep Disturbance

[0008] Humans cycle repeatedly through four stages of sleep, eachapproximately 1½-2 hours long. Rapid eye movement (REM) sleep,associated with dreaming, occurs during Stage 1 sleep at the end of eachcycle. Non-REM sleep occurs during Stage 3 and 4. When sleep quality isdisturbed due to, for example, shallow sleep, frequent awakenings, orearly awakenings, patients complain of “zombie”, “zonked”, “groggy”, or“spacey” feelings, tiredness, feelings of being “run down,” and havingdifficulty concentrating during waking hours. (The terms “zombie” and“spacey” are English slang words used to describe a state of mindwherein disconnected thoughts may be frequent and/or one may experienceimpaired short-term memory and/or concentration.)

[0009] 1.3 Fibromyalgia Syndrome

[0010] Fibromyalgia syndrome (FMS), also known as fibrositis, is achronic, non-inflammatory rheumatic disorder. The American College ofRheumatology (ACR) published a classification criteria for FMS in 1990.[Wolfe, F., et al., “The American College of Rheumatology 1990 criteriafor the classification of Fibromyalgia: Report of the MulticenterCriteria Committee,” Arthritis and Rheumatism 33:160-172 (1990)].

[0011] Some practitioners further classify fibromyalgia into twocategories—primary or secondary-concomitant fibromyalgia. Generally,primary fibromyalgia syndrome can be considered fibromyalgia occurringin the absence of another significant condition whereassecondary-concomitant fibromyalgia can be considered fibromyalgiaoccurring in the presence of another significant rheumatic disorder,which may have been caused by or is merely associated with the patient'sfibromyalgia. Secondary or concomitant fibromyalgia can includefibromyalgia in patients with classical or definite rheumatoidarthritis, osteoarthritis of the knee or hand, low back pain syndromes,cervical pain syndromes (or combinations thereof).

[0012] Studies exploring the relationship between sleep disturbances andfibromyalgia have been conducted. For example, Moldofsky et al. observedthat seven fibromyalgia patients had alpha rhythm contamination in stage4 sleep (non-REM sleep) and three fibromyalgia patients had an entireabsence of delta waves (a hallmark of stage 4 sleep). [Moldofsky, H., etal., “Musculoskeletal symptoms and non-REM sleep disturbance in patientswith ‘fibrositis syndrome’ and healthy subjects,” Psychosom. Med.37:341-51 (1975)] In another study, selected individuals who were notsuffering from fibromyalgia prior to commencement of the study, weresubjected to noise that artificially disrupted their slow-wave sleep.They experienced a similar alpha EEG sleep anomaly and complained ofnonrefreshing sleep and diffuse myalgia/fatigue (Moldofsky, H. and P.Scarisbrick, “Induction of neurasthenic musculoskeletal pain syndrome byselective sleep stage deprivation,” Psychosom. Med. 38:35-44 (1976)).The subjects did not show any increased muscle tenderness when deprivedof REM sleep (Moldofsky, et al., 1976, supra).

[0013] Various drugs including analgesics, anti-inflammatory agents,psychotropic drugs, such as tricyclic antidepressants (TCAs), or highdoses of cyclobenzaprine have been used with some success to treat somefibromyalgia patients.

[0014] TCAs have been typically administered in a dosage range of tensof milligrams/day with increasing dosages as needed. [Wysenbeek, J. etal. “Imipramine for the treatment of fibrositis: a therapeutic trial”,Ann. Rheum. 44:752-753 (1985); Carette, S. et al. “Evaluation ofamitriptyline in primary fibrositis”, Arthritis Rheum, 29: 655-659(1986); Goldenberg, D. L., “A Review of the Role of TricyclicMedications in the Treatment of Fibromyalgia Syndrome,” J. Rheumatology16:137-139, 139 (1989); Bryson, H. M. et al., “Amitriptyline: A Reviewof its Pharmacological Properties and Therapeutic Use in Chronic PainStates,” Drugs & Aging 8:459-476, 461 (1996)].

[0015] Cyclobenzaprine has been administered to fibromyalgia patientstypically in a dosage range of tens of milligrams per day. For example,several studies reported treatments of fibromyalgia or fibrositis using10 to 40 mgs of cyclobenzaprine per day. [Bennett, R. et al. “Acomparison of cyclobenzaprine and placebo in the management offibrositis,” Arthritis Rheum., 31:1535-1542 (1988); Hamaty, Daniel etal., “The plasma endorphin, prostaglandin, and catecholamine profile ofpatients with fibrositis treated with cyclobenzaprine and placebo: a5-month study,” J. Rheumatol., 16:140-143 (1989); Quimby, Lucy G. etal., “A randomized trial of cyclobenzaprine for the treatment ofFibromyalgia”, J. Rheumatol., 16:140-143 (1989)].

[0016] In another study, twelve fibromyalgia patients treated withtwenty to forty mgs of cyclobenzaprine per day did not experiencedecreased pain, as monitored by tender point count and dolorimetrymeasurements. (Reynolds, W. J., et al., “The effects of cyclobenzaprineon sleep physiology and symptoms in patients with Fibromyalgia,” J.Rheumat. 18:452-4 (1991)). Furthermore, the cyclobenzaprine did notfavorably change the alpha non-REM EEG sleep anomaly (stage IV sleep)and mood ratings of the fibromyalgia patients. Thus, no specific effectof cyclobenzaprine in that dosage range on sleep physiology wasdocumented.

[0017] Santandrea et al. compared two groups of fibromyalgia patientstreated with either 10 mg/day or 30 mg/day of cyclobenzaprine.[Santandrea, S., et al., “A Double-Blind Crossover Study of TwoCyclobenzaprine Regimens in Primary Fibromyalgia Syndrome,” J. Int. Med.Res. 21:74-80 (1993)] While both regimens resulted in a decline in thenumber of tender points and improvement in the quality of sleep,anxiety, fatigue, irritable bowel syndrome and stiffness of the patient,no significant difference in efficacy between the two therapeuticregimens was observed at any stage during the trial.

[0018] The only report of treatment with lower doses of cyclobenzaprinewas anecdotal in its results. Miller et al. reported that somefibromyalgia patients responded “favorably” to treatment with five mgsper day of cyclobenzaprine, but did not indicate what the response wasor its affect on sleep. [Miller, D. R. and R. D. Seifert, “TherapyReviews: Management of Fibromyalgia, a Distinct Rheumatologic Syndrome,”Clinical Pharm. 6:778-786, 785 (1987)].

[0019] Prior to this invention, the use of very low doses ofcyclobenzaprine (i.e., a dosage regimen of less than 5 mg/day) todecrease sleep disturbances and alleviate the symptoms of fibromyalgia(e.g. pain, sleep disturbance) had not been reported.

[0020] 1.4 Fatigue/Chronic Fatigue Syndrome

[0021] The United States Centers for Disease Control and Preventioncharacterize self-reported, persistent fatigue of 1 month or longer asprolonged fatigue. [http://www.cdc.gov/ncidod/diseases/cfs/defined3.htm;Jul. 16, 1999]. Chronic fatigue is defined as self-reported persistentor relapsing fatigue of 6 or more consecutive months (Id.).

[0022] Chronic fatigue syndrome (“CFS”) is a clinically definedcondition characterized by severe disabling fatigue and a combination ofsymptoms that prominently features self-reported impairments inconcentration and short-term memory, sleep disturbances, andmusculoskeletal pain. Chronic fatigue syndrome has also been referred toas “chronic fatigue and immune dysfunction syndrome” or “myalgicencephalitis”.

[0023] Applicant believes that chronic fatigue syndrome and fibromyalgiaare part of the same pathophysiological entity, wherein the dominantsymptom of one subset of patients is fatigue, in others it is muscularpain, and in others it is both fatigue and muscular pain. There arecertain symptoms (fever, swollen glands for example), however, which arefound in a higher percentage of CFS patients than those with FMS. Thesesymptoms, which manifest in a relatively small percentage of the totalpopulation of CFS patients, have been hypothesized to be attributable toa chronic infection by a viral agent, such as cytomegalovirus or EpsteinBarr virus.

[0024] The use of very low dose cyclobenzaprine to treat prolongedfatigue, chronic fatigue or chronic fatigue syndrome has not beenreported

SUMMARY OF THE INVENTION

[0025] An object of this invention is to provide methods andcompositions for treating a human suffering from sleep disturbances.Accordingly, the present invention relates to methods and compositionsfor treating or preventing sleep disturbances in humans using very lowdoses of cyclobenzaprine or metabolites thereof.

[0026] The methods and compositions of the invention are useful intreating sleep disturbances in general. Such sleep disturbances may becaused by stress or anxiety, disease, pain, the administration of a drugsuch as benzodiazepines, barbiturates, or alcohol. They are particularlyuseful in treating sleep disturbances caused by, exacerbated by orassociated with fibromyalgia syndrome, prolonged fatigue, chronicfatigue, chronic fatigue syndrome, a sleep disorder, a psychogenic paindisorder, chronic pain syndrome (type II), the administration of a drug,autoimmune disease, stress or anxiety.

[0027] In another embodiment, this invention provides methods andcompositions for treating a human suffering from an illness caused by orexacerbated by sleep disturbances, and symptoms of such illness. Suchillnesses include fibromyalgia, prolonged fatigue, chronic fatigue andchronic fatigue syndrome, sleep disorder, psychogenic pain disorder, andchronic pain syndrome. In the context of this embodiment of theinvention, applicant has found that administration of less than 5 mg/dayqHS of cyclobenzaprine is not only surprisingly effective at treatingthe sleep disturbance of many patients who suffer from fibromyalgia, andthose other diseases, but the patients also experienced relief fromfatigue and diffuse pain. Without wishing to be bound by theory,applicant believes cyclobenzaprine given at very low dose unexpectedlyalleviates sleep disturbances and deepens sleep, which may be importantfor treating fibromyalgia and other illnesses associated with sleepdisturbances.

[0028] Another object of this invention is to provide methods andcompositions for treating sleep disturbances in a human who usuallydeepens sleep through exercise during waking hours but who cannotbecause of injury.

[0029] Another object of this invention is to provide improved methodsand compositions for treating somatised symptoms, including pain, inpatients suffering from irritable bowel syndrome and tension headaches,associated with fibromyalgia, chronic fatigue syndrome, psychogenic paindisorders, or chronic pain syndromes.

[0030] In still a further embodiment of this invention, the methods ofthis invention comprise the administration of very low doses ofcyclobenzaprine or a metabolite thereof with one or more therapeuticagents such as a tricyclic antidepressant (TCA), a selectiveserotonin-reuptake inhibitor (SSRI); an atypical antidepressant; ananti-inflammatory agent; or an analgesic. In addition to working withthese drugs to alleviate symptoms of underlying physiological problems,cyclobenzaprine also treats sleep disturbances caused by theadministration of these drugs.

[0031] In another embodiment, the methods of this invention furthercomprise the administration of very low doses of cyclobenzaprine or ametabolite thereof in combination with psychotherapy or light-boxtherapy.

[0032] Another object of this invention is to provide a compositioncomprising a very low dose of cyclobenzaprine or a metabolite thereof asa single unit or composition that is pre-prepared into separableportions that comprise a very low dose of cyclobenzaprine or metabolitethereof, which composition is better for treating patients and aidingpractitioners to determine appropriate dosage regimens for patients.Such compositions, as well as the other compositions of this invention,may additionally comprise one or more therapeutic agents such as a TCA,a SSRI, an atypical antidepressant, an anti-inflammatory or ananalgesic.

[0033] These and the other objects of this invention are accomplished bymethods and compositions characterized by very low dosage regimens ofcyclobenzaprine. Such methods and compositions unexpectedly treat orprevent sleep disturbances.

DETAILED DESCRIPTION OF THE INVENTION

[0034] In these applications the following terms are used:

[0035] “Chronic fatigue”: a persistent or relapsing fatigue of 6 or moreconsecutive months. In a preferred embodiment, the symptom to be treatedis fatigue.

[0036] “Chronic fatigue syndrome” or “CFS”: a chronic, remitting,debilitating disorder, which predominantly features self-reportedimpairments in concentration and short-term memory, and disturbances insleep and emotions. CFS patients as defined herein should haveself-reported persistent or relapsing fatigue of 6 or more consecutivemonths. Symptoms of chronic fatigue syndrome are known in the art. In apreferred embodiment, the symptom to be treated is fatigue.

[0037] “Chronic pain syndrome” or “CPS”: two types of chronic pain: (i)chronic pain arising from identifiable, ongoing illnesses (e.g., injury,cancer, arthritis), wherein the cause of the pain is evident or (ii)chronic pain which is a psychologic-physiologic disability arising froman unidentifiable or a seemingly unexplainable source. The term chronicpain syndrome is most often used in conjunction with the latter type ofCPS (type II above). The latter type CPS, which does not necessarilyrespond to traditional pain remedies such a narcotics, has been referredto as a learned response syndrome which seems to involve aself-perpetuating alteration in pain perception and an amplifiedresponse to the perceived pain. CPSs according to this invention includechronic fatigue syndrome (CFS), myalgia encephalitis, fibrositis andfibromyalgia syndrome. Symptoms of chronic pain syndrome are known inthe art.

[0038] “Cyclobenzaprine or metabolite thereof”: includes cyclobenzaprineor a metabolite thereof or prodrugs of cyclobenzaprine or a metabolitethereof, in the form of a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

[0039] “Fibromyalgia” (or “fibromyalgia syndrome”): a chronic,non-inflammatory rheumatic disorder traditionally characterized bystiffness or diffuse pain, aches, muscle soreness, sleep disturbances orfatigue. The pain is generally widespread and generally localized atspecific “tender points,” which may bring on widespread pain and musclespasm when touched. Other symptoms include mental and emotionaldisturbances such as poor concentration and irritability,neuropsychiatric symptoms such as depression and anxiety, jointswelling, headache, numbness.

[0040] “Prolonged fatigue”: a persistent fatigue of 1 month or longer.In a preferred embodiment, the symptom to be treated is fatigue.

[0041] “Psychogenic pain disorder”: a pain syndrome exacerbated orcaused predominantly by psychological factors, in accordance with theDiagnostic and Statistical Manual of Mental Disorders (DSM-IV) [AmericanPsychiatric Association: Diagnostic and Statistical Manual of MentalDisorders, Fourth Edition. Washington, D.C., American PsychiatricAssociation, 1994]. According to the DSM-IV, pain associated with ageneral medical condition alone, absent psychological contributingfactors, is a purely physical syndrome that should not be characterizedas a mental disorder. Accordingly, the term “psychogenic pain disorder”is used herein to denote pain with a clinically significantpsychological aspect. Acute psychogenic pain disorder is characterizedby pain lasting less than 6 months, while chronic psychogenic paindisorder is characterized by pain longer than 6 months in duration. Theessential feature of psychogenic pain disorder is pain that is thepredominant focus of the clinical presentation and is of sufficientseverity to warrant clinical attention. The pain causes significantdistress or impairment in social, occupational, or other important areasof function. Symptoms of psychogenic pain disorders are known in theart.

[0042] “Sleep disorder”: any one of our major categories of sleepdysfunction. (DSM-IV, pp. 551-607; See also The InternationalClassification of Sleep Disorders: (ICSD) Diagnostic and Coding Manual,1990, American Sleep Disorders Association.) One category, primary sleepdisorders, comprises sleep disorders that do not result from anothermental disorder, a substance, or a general medical condition. Theyinclude without limitation primary insomnia, primary hypersomnia,narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleepterror disorder, sleepwalking disorder, REM sleep behavior disorder,sleep paralysis, day/night reversal and other related disorders;substance-induced sleep disorders; and sleep disorders due to a generalmedical condition. A second category comprises those sleep disordersattributable to substances, including medications and drugs of abuse. Athird category comprises sleep disturbances arising from the effects ofa general medical condition on the sleep/wake system. A fourth categoryof sleep disorders comprises those resulting from an identifiable mentaldisorder such as a mood or anxiety disorder. Symptoms of each categoryof sleep disorder are known in the art.

[0043] “Sleep disturbance”: an impairment in refreshing sleep. Such aclinical diagnosis may be made based on a patient's self describedfeeling of fatigue upon waking or the patient's report of poor qualitysleep. Such impediments to good quality sleep may be described asshallow sleep or frequent awakenings which may be associated with alpharhythm contamination in stage 4 sleep (non-REM sleep) or absence ofdelta waves during deeper physically restorative sleep. Such “sleepdisturbances” do not rise to the level of a “sleep disorder” as definedin the DSM-IV, although they may share one or more symptom in common.Symptoms of sleep disturbances are known in the art. Among them are“zombie”, “zonked”, “groggy”, or “spacey” feelings, tiredness, feelingsof being “run down,” and having difficultly concentrating during wakinghours.

[0044] “Somatization”: an unconscious process whereby psychologicaldistress or anxiety is expressed as a physical symptom.

[0045] “Very low dose” or “very low dosage regimen”: the administrationof less than 5 mg/day of cyclobenzaprine or metabolite thereof.

[0046] Cyclobenzaprine: A compound having the chemical formula:

[0047] Metabolites of cyclobenzaprine useful according to the methods ofthis invention are metabolites that have substantially the same activityor better as cyclobenzaprine in alleviating sleep disturbances or one ofmore of the symptoms of his/her illness. Cyclobenzaprine metabolitesthat may be useful according to this invention include CBP10,11-trans-dihydriol, N-desmethyl-2-hydroxycyclobenzaprine,3-hydroxycyclobenzaprine, N-desmechylcyclobezaprine cyclobenzaprineN-oxide or a chiral isomer of these metabolites.

[0048] “Cyclobenzaprine” as used in describing the invention alsoincludes prodrugs, i.e. drugs that are metabolized in vivo into theactive agent. Prodrugs useful according to this invention are those thathave substantially the same activity or better than cyclobenzaprine inalleviating sleep disturbance or one of more of the symptoms of his/herillness. Methods for making such prodrugs are readily know in the art(e.g., Balant, L. P., “Prodrugs for the Improvement of Drug AbsorptionVia Different Routes of Administration,” Eur. J. Drua Metab.Pharmacokinet. 15:143-153 (1990); and Bundgaard, H., “Novel ChemicalApproaches in Prodrug Design,” Drugs of the Future 16:443-458 (1991);incorporated by reference herein).

[0049] Pharmaceutically salts of cyclobenzaprine useful according to themethods of this invention are salts prepared from pharmaceuticallyacceptable non-toxic acids including inorganic acids and organic acids.In one preferred embodiment, the salt is a hydrochloride salt.

[0050] A composition according the present invention comprises less than5 mg of cyclobenzaprine or a metabolite thereof as a single unit(hereinafter, “composition”), or as a unit that is pre-prepared intoseparable portions (hereinafter, “separable composition”), each portionof which comprises a very low dose of cyclobenzaprine or metabolitethereof. In one embodiment, the composition or each portion of theseparable composition comprises less than or equal to 2.5 mgs ofcyclobenzaprine or metabolite thereof. In another embodiment, thecomposition or each portion of the separable composition comprises lessthan or equal to 1 mg of cyclobenzaprine or metabolite thereof. Forexample, a separable composition is a scored tablet.

[0051] A composition according the present invention may also compriseless than 5 mg of cyclobenzaprine or a metabolite thereof given withother therapeutic agents according to this invention, including a TCA,an SSRI, an atypical antidepressant, an anti-inflammatory, or ananalgesic. Thus, the composition or separable composition according tothis invention can comprise one or more TCA, SSRI, atypicalantidepressant, SNRI, anti-inflammatory, and/or analgesics.

[0052] An atypical antidepressant according to this invention areantidepressants which are not TCAs or SSRIs, e.g., serotonin agonist andreuptake inhibitors (SARIs) such as nefazodone (Serzone™) or trazodone(Desyrel™); Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs) such asbupropion (Wellbutrin™); and norepinephrine reuptake inhibitors (NRIs)such as reboxetine (Edronax™) and serotonin-norepinephrine reuptakeinhibitors (SNRIs) such as venlafaxine (Effexor™), amoxapine andmaprotiline. In a preferred embodiment, the therapeutic agent is a TCAand/or SSRI.

[0053] In one embodiment, the TCA is administered in a dose less than 25mg/day. A TCA according to this invention may be selected from the groupconsisting of imipramine, trimipramine, nortriptyline, amitriptyline,doxepin, protriptyline, clomipramine, or desipramine. In a preferredembodiment, the TCA is nefazodone (Serzone™).

[0054] In another embodiment, the SSRI is administered in a dosage of 40or less mg per day. An SSRI according to this invention may be selectedfrom the group consisting of fluoxetine (Prozac™), fluvoxamine maleate(Luvox™), paroxetine (Paxil™, Seroxar™, or Aropax™), sertraline(Zoloft™), and citalopram (Celexa™). In a preferred embodiment, the SSRIis sertraline (Zoloft™).

[0055] Said therapeutic agent according to the methods of this inventionmay be administered before, during or after the administration ofcyclobenzaprine.

[0056] The methods and compositions of this invention are useful fortreating or preventing a sleep disturbance.

[0057] In a preferred embodiment, the sleep disturbance is associatedwith the group consisting of fibromyalgia syndrome, prolonged fatigue,chronic fatigue, chronic fatigue syndrome, a sleep disorder, apsychogenic pain disorder, and chronic pain syndrome (type II).

[0058] In a more preferred embodiment, the symptoms to be treated areselected from the group consisting of “zombie”, “zonked”, “groggy”, or“spacey” feelings, tiredness, feelings of being “run down,” and havingdifficultly concentrating during waking hours.

[0059] According to the methods of this invention, one or more of theabove-identified symptoms are alleviated in fibromyalgia patients. Inone preferred embodiment, the symptom of pain is alleviated.

[0060] The methods and compositions of this invention are useful fortreating sleep disturbances in primary and secondary-concomitantfibromyalgia syndrome.

[0061] The methods and compositions of this invention are also usefulfor treating people that have sleep disturbance caused by theadministration of drugs that cause sleep disturbances, such asbenzodiazepines, barbiturates and alcohol. Benzodiazepines includechlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam,prazepam, alprazolam, chlonazepam, flunitrazepam, lorazepam, midazolam,oxazepam, quazepam, temazepam, and troazolam. Barbiturates includephenobarbital, amobarbital, probarbital, butabarbital, mephobarbital,pentobarbital, secobarbital, and talbutal.

[0062] The methods and compositions of this invention are also usefulfor treating a human suffering from an autoimmune disease, or a humansuffering from or expected to suffer from stress or anxiety.

[0063] According to the methods of this invention, very low dosecyclobenzaprine or metabolites thereof, may be administered sequentiallyor concurrently with other standard treatments for sleep disturbance,fatigue, stress, anxiety, fibromyalgia, prolonged pain, chronic pain,chronic fatigue syndrome, sleep disorders, psychogenic pain disorders,or chronic pain syndromes.

[0064] The period of treatment should be carried out for as long asnecessary to alleviate one or more of the symptoms of the illness beingtreated, either in a single, uninterrupted session of visits or indiscrete sessions. In a preferred embodiment, if a sleep disturbance isbeing treated, the treatments will preferably-be carried out such thatthe patient achieves deep, refreshing sleep. Deep, refreshing sleep isnot be confused with sleep which is merely longer in duration.Alternatively, treatments may be carried out until the patient feels anincreased energy or a greater sense of well being. Generally,cyclobenzaprine therapy can be carried out indefinitely to alleviate thesymptoms of interest and frequency of dosage may be changed to be takenas needed.

[0065] Any suitable route of administration may be employed forproviding the patient with an effective dosage of cyclobenzaprine. Forexample, oral, rectal, parenteral, transdermal, subcutaneous,sublingual, intranasal, intramuscular, intrathecal and the like may beemployed as appropriate. The term parenteral as used herein includessubcutaneous, intracutaneous, intravenous, intramuscular,intra-articular, intrasynovial, intrasternal, intrathecal, intralesionaland intracranial injection or infusion techniques.

[0066] Dosage forms include tablets, scored tablets, coated tablets,caplets, capsules (e.g. hard gelatin capsules), troches, dragées,dispersions, suspensions, solutions, patches and the like, includingsustained release formulations well known in the art. In one preferredembodiment, the dosage form is a scored tablet.

[0067] The compositions and separable compositions useful according tothis invention include those suitable for oral, rectal, transdermal,sublingual, and parenteral administration (including subcutaneous,intramuscular, intrathecal and intravenous), although the most suitableroute in any given case will depend on the nature and/or severity of thecondition being treated. A preferred route of administration accordingto the methods of the present invention is the oral route. Thecomposition may be conveniently presented in unit dosage form andprepared by any of the methods well-known in the art of pharmacy.

[0068] The compositions or separable compositions of this invention maybe orally administered in any orally acceptable dosage form including,but not limited to, capsules, tablets, and aqueous suspensions andsolutions. In the case of tablets for oral use, carriers which arecommonly used include lactose and corn starch. Lubricating agents, suchas magnesium stearate, are also typically added. For oral administrationin a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening and/or flavoring and/or coloring agents maybe added.

[0069] The compositions according to this invention may be in the formof a sterile injectable preparation, for example, as a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween 80) andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersantsuch as Ph. Helv or a similar alcohol.

[0070] Compositions or separable compositions of this invention may alsobe administered in the form of suppositories for rectal administration.These compositions or separable compositions can be prepared by mixing acompound of this invention with a suitable non-irritating excipientwhich is solid at room temperature but liquid at the rectal temperatureand therefore will melt in the rectum to release the active components.Such materials include, but are not limited to, cocoa butter, beeswaxand polyethylene glycols.

[0071] The composition of this invention may be administered by nasalaerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

[0072] A typical oral formulation for coated tablets would consist ofthe following: Formula Quantity per Tablet (mg.) cyclobenzaprine  1.0Lactose 74.0 Corn Starch 35.0 Water (per thousand Tablets) 30.0 ml*Magnesium Stearate  1.0 Corn Starch 25.0

[0073] The active ingredient (cyclobenzaprine) is blended with thelactose until a uniform blend is formed. The smaller quantity of cornstarch is blended with a suitable quantity of water to form a cornstarch paste. This is then mixed with said uniform blend until a uniformwet mass is formed. The remaining corn starch is added to the resultingwet mass and mixed until uniform granules are obtained. The granules arethen screened through a suitable milling machine, using a ¼ inchstainless steel screen. The milled granules are then dried in a suitabledrying oven until the desired moisture content is obtained. The driedgranules are then milled through a suitable milling machine using ¼ meshstainless steel screen. The magnesium stearate is then blended and theresulting mixture is compressed into tablets of desired shape,thickness, hardness and disintegration.

[0074] Tablets are coated by standard aqueous or nonaqueous techniques.For example, 2.5 mg of hydroxypropymethylcellulose can be dissolved in25 mg of deionized water. An aqueous (10 mg) suspension of 1.88 mg talc,0.5 mg of titanium dioxide, 0.1 mg of yellow iron oxide, and 0.02 mg ofred iron oxide is stirred into this solution. The coating suspension issprayed on the tablets and the coated tablets are dried overnight at 45°C.

[0075] Quantification of improvement may be measured according tomethods known in the art. For example, pain may be measured using tenderpoint count, the McGill Pain Questionnaire, the Arthritis ImpactMeasurement Scales (AIMS), the Sickness Impact Profile (SIP), the HealthAssessment Questionnaire (HAQ) functional disability index, the SymptomChecklist-90R, and dolorimeter scores. A practitioner may reliablyassess changes in condition by comparing treatment results over a timespan. (Alarcon, Graciela, et al., “Advances in the Treatment ofFibromyalgia: Current Status and Future Directions”, Am. J. Med.Sciences, 315:397-404 (1998).)

[0076] The quality of sleep (“sleep disturbance”) may be determined,inter alia, by asking the patient if he/she awakened tired ornonrefreshed “never,” “seldom,” “often or usually,” or “always.” Repliesof “often or usually” or “always” may be scored as positive and otherreplies as negative. Patients reports of well-being or relief from“zombie” or “spacey” feelings, feelings of being “run down,” and havingdifficultly concentrating during waking hours are indications of betterquality of sleep or deep, refreshing sleep.

[0077] The magnitude of a prophylactic or therapeutic dose of the activeingredient (i.e., cyclobenzaprine or metabolite thereof) in theprevention or treatment of a human will vary with the type ofaffliction, the severity of the patient's affliction and the route ofadministration. The dose and dose frequency will also vary according tothe age, weight and response of the individual patient. However, thedosage will not equal or exceed 5 mgs per day. In a preferredembodiment, one dose is given at bed time or up to several hours beforebedtime to facilitate the achievement of deep, refreshing sleep. Bedtimemay be any hour of the day at which a person engages in the mostextensive period of sleep.

[0078] The treating physician will know how to increase, decrease orinterrupt treatment based upon patient response. Generally, however,treatment or prevention of an illness treated according to the methodsof this invention will be timed to coincide with exposure tobiochemical, environmental, or hormonal stimuli likely to trigger sleepdisturbance, illnesses treatable according to this invention or symptomsthereof.

[0079] The various terms described above such as “therapeuticallyeffective amount,” are encompassed by the above-described dosage amountsand dose frequency schedule.

[0080] Throughout this specification and claims, the word “comprise,” orvariations such as “comprises” or “comprising,” will be understood toimply the inclusion of a stated integer or group of integers but not theexclusion of any other integer or group of integers.

[0081] In order that this invention be more fully understood, thefollowing examples are set forth. These examples are for the purpose ofillustration only and are not to be construed as limiting the scope ofthe invention in any way.

EXAMPLES Example 3

[0082] A. S., a 27 year old female homemaker, had been diagnosed withfibromyalgia ten years previously, but had done well on no medicationuntil exacerbation of disease activity post-partem two years prior topresentation. Symptoms then subsided until the 26th week of her secondpregnancy, when she was seen in rheumatologic consultation complainingof multiple areas of soreness and fatigue, associated with disruptedsleep. On examination she had a total of 16 tender points, withunremarkable bloodwork including thyroid functions and ESR. Afterdelivery, with continued symptoms (the patient was not breast feeding),she was begun on cyclobenzaprine ½ of a 10 mg tablet qHS, but shetelephoned to state that she felt “like a zombie.” On a dosage of ¼tablet (2.5 mg) qHS she subsequently found progressive improvement. Shereported complete abatement of multiple areas of soreness, aches andpains and disrupted sleep.

Example 4

[0083] G. R., a 49 year old female executive, presented with fatigue andpoor sleep and diffuse pain, and on examination had tenderness overbilateral trochanters, bilateral medial knees, and paralumbar areas.Bloodwork was unremarkable, and her previous imipramine 10 mg p.o. qHSwas changed to cyclobenzaprine, 10 mg p.o. qHS, but the dose had to bereduced to ½ tablet (5 mg) due to mental cloudiness. After her symptomsabated, she discontinued treatment. However, six years later hersymptoms recurred, with similar findings in the office, but this time ½tablet (5 mg) left her “groggy” in the morning. She was on a dose of ⅓tablet of cyclobenzaprine (3 33 mg). The treatment alleviated hersymptoms with no adverse effects. She achieved complete resolution ofher tender points and reported that she experienced improved energy anddeep sleep.

Example 5

[0084] M. W., an 80 year old widow, complained of occasional periods ofpoor sleep with frequent awakening and resultant exhaustion. The patientwas prescribed cyclobenzaprine 10 mg p.o. qHS, which helped her sleepbut caused “grogginess” during the day as did ½ tablet (5 mg). Thepatient's dosage regimen was switched to ¼ tablet (2.5 mg) per day qHS.The patient reported that the new dosage regimen helped her to sleepdeeply, allowing her to awaken refreshed without any adverse mentaleffect.

Example 6

[0085] C. S., a 35 year old female homemaker, presented with complaintsof chest pain previously attributed to her known history of mitral valveprolapse. She also complained of a several year history of fatigue. Onphysical exam she exhibited focal tenderness of the parasternal area(reproducing her chest pain), as well as her paracervical, bilateralmedial epichondyles medial knees, and paralumbar areas. Her exam wasotherwise normal except for a midsystolic click. Comprehensivebloodwork, including thyroid function testing and erythrocytesedimentation rate (ESR), was unremarkable. The diagnosis offibromyalgia was made, and she was begun on cyclobenzaprine, 10 mg p.o.qHS, but on telephone followup she complained of feeling “groggy,” andtherefore her dose was decreased to ¼ to ½ tablet (approximately 2.5-5mg). She felt markedly improved on this dose, with a feeling of deepersleep, and with resolution of both her chest pain and other sore areas,and of her fatigue.

Example 7

[0086] M. T., a 68 year old active grandmother, presented with the newonset of cervical and lumbar muscular pains associated with poor qualitysleep and fatigue. The patient was diagnosed with fibromyalgia. Physicaltherapy did not help significantly, and although she was averse tomedication, agreed to a trial of cyclobenzaprine, 10 mg p.o. qHS. Intelephone followup she found this dose to be helping her muscular pains.She experienced dry mouth and constipation. On 5 mg, the side effectscontinued and wanted to discontinue the medication entirely. However, on¼ pill (2.5 mg), she found this dose to be very effective for both hermuscular pains and her sleep disturbance and fatigue with no sideeffects.

Example 8

[0087] H. P., a 41 year old female homemaker, presented with complaintsof diffuse pain and fatigue. Examination revealed multiple tender pointsin the parasternal and paralumbar areas, as well as tenderness of medialknees, without evidence of synovitis. Comprehensive bloodwork, includingthyroid function testing and ESR, was unremarkable. She was diagnosedwith fibromyalgia and was begun on cyclobenzaprine, 10 mg P.o. qHS, butcomplained of increased A.M. fatigue and constipation; however, shesubsequently did well when prescribed ¼ to ½ (2.5-5 mg) tablet. Shedemonstrated improved sleep, decreased muscular pain, and improved senseof well-being.

Example 9

[0088] C. M., a 43 year old female homemaker, presented with complaintsof right trapezius spasm. She had recently been started on paroxetine,20 mg p.o. qd for mild depression, and had also noted disrupted sleepquality with frequent awakening with resultant fatigue and daytimesomnolence. Her pains subsequently generalized to involve multiple areasof soft tissue pain, and on examination she had sixteen tender pointsthat were exquisitely sensitive to moderate pressure. Comprehensivebloodwork, including thyroid function testing, was unremarkable. She wasdiagnosed with fibromyalgia and was begun on cyclobenzaprine 10 mg p.o.qHS for the diagnosis of fibromyalgia and possible sleep disturbance dueto the SSRI paroxetine. In followup she complained of feeling “zonked”in the morning on 10 mg. Subsequently she did well when she wasprescribed ¼ to ½ (2.5-5 mg) cyclobenzaprine qHS.

Example 10

[0089] M. P., a 29 year old female homemaker, had recently given birthto a healthy baby, and in during the later stages of pregnancy and inthe post-partem period noted fatigue and exhaustion associated withmultiple areas of muscular soreness. On examination she exhibitedtenderness over both medial epichondyles and her right trapezius muscle.(She was examined on a “good day,” and by history had multiple othersimilarly tender areas.) She was diagnosed with fibromyalgia and wasbegun on cyclobenzaprine, 10 mg p.o. qHS but noted prompt increase inher A.M. fatigue. On ½ tablet (5 mg), she continued to feel “zonkedout.” Subsequently on ¼ tablet (2.5 mg), she did not experience sideeffects however at this dose it did not help her pains. She subsequentlydid well on a trial of nortriptyline.

Example 11

[0090] K. L., a 48 year old female executive, presented with complaintsof “burning pains” in her muscles, associated with sleep disturbancewith frequent awakening and resultant fatigue. Her symptoms had begunsoon after she had been treated with sertraline for mild depression.Examination showed multiple tender points, absence of synovitis, andcomprehensive bloodwork including thyroid functions and ESA wasunremarkable. She was diagnosed with fibromyalgia and was begun oncyclobenzaprine 10 mg p.o. qHS, but complained of feeling “groggy” inthe A.M. When prescribed ¼ to ½ tablet (2.5-5 mg), she noted significantimprovement in her sleep and muscle pain, with an increase in her energylevel.

Example 12

[0091] J. T., a 50 year old executive, had been tried on multiplemedications by a “fibromyalgia specialist,” who according to the patienthad performed over $2,000 in blood tests, diagnosing “yeast infection inthe blood” and multiple allergies. The patient indeed did havefibromyalgia with multiple tender points and unremarkable bloodwork. Shewas treated with ¼ to {fraction (1/2 )} tablet (2.5-5 mg) ofcyclobenzaprine and telephoned soon thereafter to report “the cloud haslifted;” she felt markedly improved with deeper sleep, improved energyand decreased fatigue, and decrease in muscle pain.

Example 13

[0092] J. H., a 53 year old female school teacher, presented withlongstanding fatigue and muscle soreness. On examination, she had 16tender points and unremarkable comprehensive bloodwork, includingthyroid function testing and ESR. She was diagnosed with fibromyalgiaand was treated with cyclobenzaprine 10 mg p.o. qHS, but found she wastoo “spacey” to function teaching in the morning, and had the sameexperience taking ½ tablet (5 mg). Despite weighing 232 lbs, a dosage of¼ tablet (2.5 mg) deepened her sleep and eliminated all of her soreness.She shortly thereafter stopped her cyclobenzaprine in order to be morearousable should her ill mother call for her in the middle of the night;this led to an immediate return of all of her previous symptoms.

Example 14

[0093] A. G., a 46 year old female homemaker, complained of disruptedsleep with frequent awakening attributed to temporary domestic stress.She was treated with cyclobenzaprine 10 mg p.o. qHS, but found she wastoo “spacey” in the morning; a dosage of {fraction (1/4 )} tablet (2.5mg) allowed her to sleep soundly without affecting her mental status.

Example 15

[0094] D. B., a 55 year old male aerospace engineer, presented withexhaustion and fatigue, concerned he was suffering from chronic Lymedisease. Upon further questioning, he had been sleeping poorly for manymonths, with frequent awakening and daytime somnolence, nearly fallingasleep at the wheel. His wife reported no loud snoring or periods ofapnea. Physical examination was unremarkable, as was comprehensivebloodwork, including Lyme serologies, thyroid function testing, and ESR.A trial of cyclobenzaprine 10 mg helped deepen his sleep, but made himfeel too “groggy” during the day; however, ¼ to ½ tablet (2.5-5 mg) ledto improved sleep and increased energy, with resolution of his daytimesomnolence.

[0095] The embodiments of the present invention described above areintended to be merely exemplary and those skilled in the art willrecognize, or be able to ascertain using no more than routineexperimentation, numerous equivalents to the specific proceduresdescribed herein. All such equivalents are considered to be within thescope of the present invention and are covered by the following claims.

[0096] The contents of all documents contained herein are herebyincorporated by reference.

I claim:
 1. A method for treating or preventing a sleep disturbancecomprising the step of administering to a human in need of treatment forsuch sleep disturbance a composition comprising cyclobenzaprine or ametabolite, prodrug, or salt thereof in an amount of less than 5 mg/day.2. The method according to claim 1 , wherein the sleep disturbance isassociated with the group consisting of fibromyalgia syndrome, prolongedfatigue, chronic fatigue, chronic fatigue syndrome, a sleep disorder, apsychogenic pain disorder, and chronic pain syndrome (type II).
 3. Themethod according to claim 1 , wherein such sleep disturbance isassociated with the administration of a drug.
 4. The method according toclaim 3 wherein the drug is a benzodiazepine.
 5. The method according toclaim 4 wherein the benzodiazepine is selected from the group comprisingchlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam,prazepam, alprazolam, chlonazepam, flunitrazepam, lorazepam, midazolam,oxazepam, quazepam, temazepam, or troazolam.
 6. The method according toclaim 3 wherein the drug causing sleep disturbance is a barbiturate. 7.The method according to claim 6 wherein the barbiturate is selected fromthe group including phenobarbital, amobarbital, aprobarbital,butabarbital, mephobarbital, pentobarbital, secobarbital, and talbutal.8. The method according to claim 3 wherein the drug is alcohol.
 9. Themethod according to claim 1 , wherein the human is suffering from anautoimmune disease.
 10. The method according to claim 1 , wherein thehuman is suffering from or is expecting to suffer stress or anxiety. 11.A method for treating or preventing fibromyalgia comprising the step ofadministering to a human in need of treatment for fibromyalgiacyclobenzaprine or a metabolite thereof in an amount of less than 5mg/day.
 12. A method for treating or preventing prolonged fatigue,chronic fatigue or chronic fatigue syndrome comprising administering toa human in need of treatment for prolonged fatigue, chronic fatigue orchronic fatigue syndrome, cyclobenzaprine or a metabolite thereof in anamount of less than 5 mg/day.
 13. A method for treating or preventing asleep disorder comprising the step of administering to a human in needof treatment for a sleep disorder cyclobenzaprine or a metabolitethereof in an amount of less than 5 mg/day.
 14. A method for treating orpreventing a psychogenic pain disorder comprising the step ofadministering to a human in need of treatment for a psychogenic paindisorder cyclobenzaprine or a metabolite thereof in an amount of lessthan 5 mg/day.
 15. A method for treating or preventing a chronic painsyndrome (type II) comprising the step of administering to a human inneed of treatment for a chronic pain syndrome (type II) cyclobenzaprineor a metabolite thereof in an amount of less than 5 mg/day.
 16. Themethod according to any one of claims 1 or 11-15, whereincyclobenzaprine or metabolite thereof is administered in an amount of2.5 mg or less per day.
 17. The method according to any one of claims 1or 11-15, wherein cyclobenzaprine or metabolite thereof is administeredin an amount of 1.0 mg or less per day.
 18. The method according to anyone of claims 1 or 11-15, wherein cyclobenzaprine or metabolite thereofis administered in one dose before bedtime.
 19. The method according toany one of claims 1 or 11-15, wherein cyclobenzaprine or metabolitethereof is administered in combination with psychotherapy.
 20. Themethod according to any one of claims 1 or 11-15, whereincyclobenzaprine or metabolite thereof is administered in combinationwith light-box therapy.
 21. The method according to any one of claims 1or 11-15, wherein cyclobenzaprine or metabolite thereof is administeredin combination with other drug therapies for treatment of the illness orsymptoms thereof.
 22. The method according to any one of claims 1 or11-15, wherein cyclobenzaprine is administered as a hydrochloride salt.23. The method according to any one of claims 1 or 11-15, furthercomprising the step of administering a therapeutic agent sequentially orconcurrently with said cyclobenzaprine or metabolite thereof.
 24. Themethod according to claim 21 , wherein the therapeutic agent is selectedfrom the group consisting of a TCA, an SSRI, an atypical antidepressant,an SNRI, an NRIS, an anti-inflammatory, or an analgesic.
 25. The methodaccording to claim 24 , wherein the TCA is selected from the groupconsisting of imipramine, trimipramine, nortriptyline, amitriptyline,doxepin, protriptyline, clomipramine and desipramine.
 26. The methodaccording to claim 24 , wherein the SSRI is selected from the groupconsisting of fluoxetine, fluvoxamine maleate, paroxetine, sertraline,and citalopram.
 27. The method according to claim 24 , wherein theatypical antidepressant is selected from the group consisting ofserotonin agonist and reuptake inhibitors (SARIs) such as nefazodone(Serzone™) or trazodone (Desyrel™); Norepinephrine-Dopamine ReuptakeInhibitors (NDRIs) such as bupropion (Wellbutrin™); and norepinephrinereuptake inhibitors (NRIs) such as reboxetine (Edronax™) andserotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine(Effexor™), amoxapine and maprotiline.
 28. The method according to anyone of claims 1 or 11-15, wherein the cyclobenzaprine or metabolitethereof is administered orally or parentally.
 29. The method accordingto any one of claims 1 or 11-15, wherein the cyclobenzaprine orpharmaceutically acceptable salt thereof is administered as a tablet ora capsule.
 30. A composition comprising less than 5 mgs ofcyclobenzaprine or a metabolite thereof as a single unit or as a unitthat is pre-prepared into separable portions, each portion of whichcomprises a less than 5 mgs of cyclobenzaprine or metabolite thereof.31. The composition according to claim 30 , wherein the single unit oreach separable portion comprises less than or equal to 2.5 mg ofcyclobenzaprine or metabolite thereof.
 32. The composition according toclaim 30 , wherein the single unit or each separable portion comprisesless than or equal to 1.0 mg of cyclobenzaprine or metabolite thereof.33. The composition according to claim 30 , further comprising atherapeutic agent.
 34. The composition according to claim 33 , whereinthe therapeutic agent is selected from the group consisting of a TCA, anSSRI, an atypical antidepressant, an SNRI, an NRIS an anti-inflammatory,or an analgesic.
 35. The composition according to claim 34 , wherein thetherapeutic agent is a TCA selected from the group consisting ofimipramine, trimipramine, nortriptyline, amitriptyline, doxepin,protriptyline, clomipramine and desipramine.
 36. The compositionaccording to claim 34 , wherein the therapeutic agent is an SSRIselected from the group consisting of fluoxetine, fluvoxamine,paroxetine, sertraline or citalopram.
 37. The composition according toclaim 34 , wherein the atypical antidepressant is selected from thegroup consisting of serotonin agonist and reuptake inhibitors (SARIs)such as nefazodone (Serzone™) or trazodone (Desyrel™);Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs) such as bupropion(Wellbutrin™); and norepinephrine reuptake inhibitors (NRIs) such asreboxetine (Edronax™) and serotonin-norepinephrine reuptake inhibitors(SNRIs) such as venlafaxine (Effexor™), amoxapine and maprotiline.